Integrated stress response (ISR) plays an essential role when cells adapt to stress conditions such as hypoxia and malnutrition (non-patent document 1). ISR is regulated by 4 kinds of eIF2α kinase (EIF2AK); heme-regulated initiation factor 2 alpha kinase (HRI), double stranded RNA-activated protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), GCN2. These EIF2AKs are activated under a particular stress and phosphorylate a protein translation initiation regulatory factor, eIF2α. It is known that GCN2 is activated by amino acid starvation, ultraviolet irradiation and the like. Phosphorylation of eIF2α by GCN2 is considered to cause expression of the activating transcription factor 4 (ATF4) at the downstream thereof and involvement in amino acid synthesis, metabolism, cell death and the like.
In the intratumoral microenvironment, angiogenesis may become locally insufficient along with abnormal proliferation of cancer cells and the like. When the hematological supply is stagnant, a state of oxygen or nutrient deficiency is induced. Cancer cells support tumor growth by having the ability to survive by overcoming these harsh environments.
It is suggested that the GCN2/eIF2α/ATF4 pathway has the possibility of playing an important role in the survival and proliferation of cells in the amino acid starved state and is involved in angiogenesis in tumor (non-patent documents 2, 3). In addition, GCN2 has been reported to show high expression in certain tumors as compared to normal tissues (non-patent document 3).
As a compound inhibiting GCN2, the compounds described in patent documents 1-3 and the like are known. However, specific disclosure of anti-cancer action and preventive and therapeutic effects on other diseases which are caused by GCN2 inhibition is absent. Non-patent document 4 discloses Raf inhibitors and patent documents 4, 5 and 6 disclose pyrimidine derivatives and compounds which are pyrimidylpyrrolopyridinone derivatives and having a sulfonamide structure for the treatment of cancer and autoimmune diseases. To date, there is no compound launched as a therapeutic agent for cancer and other diseases based on a GCN2 inhibitory action.